Bicyclo(2.2.2)octane-1-carboxylate esters of progestational steroids



United States Patent 3,485,853 BICYCLO[2.2.2]OCTANE-l-CARBOXYLATE ESTERS0F PROGESTATIONAL STEROIDS Alexander Cross, Mexico City, Mexico, andJohn H.

Fried, Palo Alto, 'Calif., assignors to Syntex Corporation, Panama,Panama, a corporation of Panama No Drawing. Filed Sept. 7, 1967, Ser.No. 665,998 Int. Cl. C07c 169/36, 173/00, 167/28 US. Cl. 260--397.4 28Claims ABSTRACT OF THE DISCLOSURE Bicyclo[2.2.2]octane 1 -carboxylate,bicyclo[2.2.2] octane-l'methylenecarbonate, and tricyclo[3.3.1.l]decane-l-methylenecarbonate esters of M-pregnane steroids which estersare useful for their long-acting anti-fertility and progestationalactivity and processes for the preparation of these novel esters.

This invention relates to new and useful steroid esters. It morespecifically pertains to novel and useful steroidalbicyclo[2.2.2]octane-1-carboxylate, bicyclo[2.2.2]octane- 1methylenecarbonate, and tricyclo[3.3.1.1 ]decane 1- methylenecarbonateesters as well as various molecularly modified derivatives thereof, thesteroid nucleus thus bearing a novel group represented by the FormulasA, B, and C:

at the C17 position with a group represented by the above Formula A.

These novel steroid esters of the present invention are of the pregnaneseries and are represented by the following Formula I:

ice

wherein R is an oxygen atom or the group in which R is hydroxy and theconventional hydrolyzable esters thereof, tetrahydropyran-Z-yloxy,tetrahydrofuran- 2-yloxy, cyclopentyloxy, or a polycyclic grouprepresented by one of the above Formulas A, B, and C; R is hydrogen,hydroxy and the conventional hydrolyzable esters thereof or a polycyclicgroup represented by the above Formula A; R is hydrogen, hydroxy,methyl, or when taken together with R alkylidenedioxy; R is hydrogen,chloro, fluoro, or methyl; R is hydrogen or methyl; each of Z and Z is acarbon-carbon single, a carbon-carbon double bond, or a methylene groupof formula in which each of X and Y is hydrogen, chloro, or fluoro; Zbeing a carbon-carbon single bond when R is other than an oxygen atomand when R is hydrogen; one of R and R being said polycyclic group.

The terms (lower)alkyl and derivations thereof appearing in the abovedefinitions and elsewhere in the instant specification denote alkylgroups containing from 1 to 6 carbon atoms, inclusive, such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, amyl, hexyl,and the like.

The term conventional hydrolyzable ester as used herein denotes thosehydrolyzable ester groups conventionally employed in the steroid art,preferably those derived from hydrocarbon carboxylic acids or phosphoricacids and their salts. The term hydrocarbon carboxylic acid defines bothsubstituted and unsubstituted hydrocarbon carboxylic acids. These acidscan be completely saturated or possess varying degrees of unsaturation(including aromatic), can be straight chain, branched chain, or cyclicstructure, and preferably contain from 1 to 12 carbon atoms. Inaddition, they can be substituted by functional groups, for example,hydroxy, alkoxy containing up to six carbon atoms, acyloxy containing upto 12 carbon atoms, nitro, amino, halogeno, and the like, attached tothe hydrocarbon backbone chain. Typical conventional hydrolyzable estersthus included within the scope of the term and the instant invention areacetate, propionate, butyrate, valerate, caproate, enanthate, caprylate,pelargonate, acrylate, undecenoate, phenoxyacetate, benzoate,phenylacetate, diphenylacetate, diethylacetate, trimethylacetate,t-butylacetate, trimethylhexanoate, methylneopentylacetate,cyclohexylacetate, cyclopentylpropionate, adamantoate, glycolate,methoxyacetate, hemisuccinate, hemiadipate, hemi-,8,f1-dimethylglutarate, acetoxyacetate, 2-chloro-4-nitrobenzoate,aminoacetate, diethylaminoacetate, piperidinoacetate, fi-chloropropionate, trichloroacetate, fi-chlorobutyrate, dihydrogen phosphate, dibenzylphosphate, benzyl hydrogen phosphate, sodium benzyl phosphate,cyclohexylammonium benzyl phosphate, sodium o-methoxyphenyl phosphate,cyclohexylammonium p-cyanobenzyl phosphate, sodium phenacyl phosphate,benzyl o-carbomethoxyphenyl phosphate, and the like.

By the term aryl" is included aryl, aralkyl, and alkaryl groups, such asphenyl, p-chlorophenyl, p-methoxyphenyl, benzyl, phenethyl, tolyl,ethylphenyl, and the like. The wavy line (i) designates and includesboth the alpha and beta configurations.

3 Thus included within the scope of the present invention are the novelsteroid esters represented by the following Formulas (I-a), (I-b),(I-c), and (Id):

bicyclo[2.2.2]octan-1-oic anhydride (preferably, (lower) alkanoicanhydride), or the corresponding C-Z unsaturated and/or C4 substitutedderivatives thereof. Alternawherein, in each formula, each of R, R, R RR R R Z, Z and Z is as hereinbefore defined.

It will be understood that the above represented compounds and the scopeof the instant invention include the corresponding novel steroidalC-3,17 bis esters.

The novel polycyclic esters of this invention possess enhanced andlong-acting anti-fertility and progestational activity. They areaccordingly useful in the control and regulation of fertility and in themanagement of various menstrual disorders.

These compounds are administered via the usual routes, whether orally orparenterally, either singly, in conjunction with other medicinal agents,or in pharmaceutically acceptable non-toxic compositions formed by theincorporation of any of the normally employed excipients. Dosage levelsvary according to the particular afiiiction or condition being treated,its degree or severity, and the observed response to treatment butgenerally a daily rate of from .01 mg. to 1 mg. per kilogram of bodyweight is satisfactory.

The novel steroid esters of the present invention are prepared via usualesterification reaction union of the polycyclic moiety with the steroidmoiety, the specific procedures conditioned upon the particular esterprepared as hereinafter set forth in more detail.

The novel pregnane steroid bicyclic esters hereof which are representedabove by Formulas (I-a) and (I-b) are prepared by esterifying thecorresponding steroidal alcohol (hydroxy at C-3 and/or C-17) either withan acid halide or acid anhydride which otherwise correspond to thegroups represented by Formula A, that is, a bicyclo [2.2.2]octan-1-oicacid halide (preferably, ch oride), a

tively, the acid per se or the esters thereof can be so employed.

In the practice of the preferred aspects of the above preparation andexcept as qualified below for the mono C-17 addition, the reaction isconducted in the presence of base, such as is provided by an organictertiary amine, for example, triethylamine, pyridine, and the like. Thereaction is also conducted with an inert solvent, such as dioxane,tetrahy-drofuran, diethyl ether, benzene, Xylene, and the like, with thereaction being carried out at temperatures of from about 0 C. to aboutC. or higher upwards of C. Temperatures below 0 C. may be employeddepending mainly upon reactants and reaction choice.

The novel monoester is introduced at C-17 by esterifying the 3-keto-A-l7hydroxy compound by the above procedure minus the amine base butincluding, instead, the

. catalytic presence of an arylsulfonic acid, such as p-toluenesulfonicacid, p-nitrobenzenesulfonic acid, and the like. This provides the17-ester of the 3-keto-A derivative as well as some of the corresponding3-enol ester. The latter is conventionally hydrolyzed such as withpotassium carbonate in methanol, to remove the C-3 enol ester group atC-17. Subsequent reduction of the 3-keto group to the 3fi-hydroXy-Aderivative and esterification as described above with amine base butwithout the need of acid catalyst, furnishes the his ester compounds.Alternatively, the thus formed 313-01 can be esterified to aconventional hydrolyzable ester to give the mixed ester compounds.

The novel monoester at C-3 is prepared by, first, selectively reducingthe 3-keto group such as with sodium borohydride in anhydrousisopropanol and thereafter esterifying as described above, with aminebase but without acid catalyst. Similarly, after the 3-hydroxyl is thusesterified to the novel ester group, the l7-hydroxyl can be converted toits conventional hydrolyzable ester giving the mixed ester compounds.Alternatively and preferred, the conventional ester is present in thestarting compounds used for the novel esterification process.

The bicyclo[2.2.2]octane and bicyclo[2.2.2]oct-2- ene-1-carboxylic acidhalides and anhydride for the above procedures are prepared from thecorresponding free acid compounds by methods known per se as described,for example, in Wagner and Zook, Synthetic Organic Chemistry, John Wileyand Sons, Inc., NY. (1953), p. 546 et. seq. and p. 558 et. seq.,respectively.

The corresponding free carboxylic acid compounds from which the acidhalides and acid anhydrides are formed are also prepared by knownmethods. One such method involves treating a 4-substituted or-unsubstituted cyclohexa-l, 3-diene-1-carboxylic acid or -1-carboxylateby the Diels-Alder addition of ethylene, such as according to theconditions set forth in US. Patent 3,081,- 334 to afford thecorresponding 4-unsubstituted or -unsubstituted bicyclo[2.2.2]octane-lcarboxylic acids. Thereafter, the thus obtained saturated acids can bedehydrogenated to the corresponding 4-substituted or -unsubstitutedbicyclo[2.2.2]oct-2-ene l carboxylic acids. Other suitable methods forpreparing these acids are set forth by Holtz et al., J. Am. Chem. Soc.,86, 5183 (1964); Kauer et al., J. Org. Chem., 30, 1431 (1965); Grob etal., Helv. Chim. Acta., 41, 1191 (1958); Roberts et al., I. Am. Chem.Soc. 75, 637 (1953); Belgium Patent 665,701; and Netherlands Patent6,507,979.

The novel pregnane steroid bicyclo carbonate esters hereof which arerepresented above by Formula Ic are prepared analogously to the methodsoperable for the preparation of the compounds of Formula I-b as setforth above utilizing, instead, the appropriate steroidal alcohol withthe chlorocarbonate (chloroformate) which otherwise correspond to thegroups represented by Formula b, that is, abicyclo[2.2.2]-octane-1-methylenechlorocarbonate or the correspondingC-2 unsaturated and/or C4 substituted derivatives thereof.

The chlorocarbonate reactants are conveniently prepared via knownprocedures. First, the corresponding free carboxylic acid compound(obtained as set forth above) is conventionally reduced such as with ametal hydride, for example, lithium aluminum hydride, and the like, ininert solvent, as described by Wagner and Zook, op. cit., p. 155 etseq., and the resultant alcohol (methylol) treated with phosgene such asaccording to the procedure described in Wagner and Zook, op. cit., p.483 et seq.

The novel pregnane steroid tricyclic carbonate esters hereof which arerepresented above by Formula I-d are prepared analogously to the methodsset forth above for the preparation of the bicyclic carbonate esterswith the substitution of the corresponding tricyclic chlorocarbonate(chloroformate) which otherwise corresponds to the group represented byFormula C above, namely, tricyclo [3.3.1.1]decane-1-methylenechlorocarbonate, in lieu of the bicyclo derivatives.

This tricyclic chlorocarbonate compound is similarly prepared fromtricyclo[3.3.1.1 ]decane-l-carboxylic acid, otherwise referred to asadamantane-1-carboxylic yielding a 3-keto-A -diene containing a 6-chloroor 6-fiuoro group, respectively.

Substituents represented by R and R are also preferably present in thestarting steroid. 16a,17a-acetals or ketals are prepared throughtreatment with a 16a,l7ahydroxy compound with an aldehyde 0r ke'tone inthe presence of an acid, such as perchloric acid.

The conjugated unsaturated system is introduced as follows. By treatinga 3-keto-A with 2,3-dichloro-5,6- dicyano-1,4-benzoquinone (D.D.Q.) in,for example, dioxane solvent, the corresponding 3-keto-A -diene isprepared. Treatment of the 3-keto-A -ene with chloranil in ethyl acetateand in the presence of acetic acid produces the corresponding 3-keto-A-diene. Similar treatment of the 3-keto-A -diene with chloranil inn-amyl alcohol affords the corresponding 3-keto-A -triene compounds.

Introduction of the halomethylene group at either of positions C1,2and/or positions C6,7 involves treatment of the conjugated unsaturatedsteroid with a molar excess of an alkali or alkaline earth metal salt ofa haloacetic acid, such as bromochloroacetic acid, dichloroacetic acid,trichloroacetic acid, chlorofiuoroacetic acid, dichloroflnoroaceticacid, chlorodifluoroacetic acid, and the like. Use of the trihalo acidintroduces the dihalomethylene group while a dihalo acid provides themonohalomethylene group.

It is preferably to conduct this latter reaction after certain labilesubstituents, such as hydroxy groups, have been protected, for example,by converting them to esters, tetrahydropyranyl ethers, or ketones whichgroups readily facilitate the regeneration of the hydroxyl. Thispreference is not an absolute necessity, however, since the hydroxylgroup which readily becomes involved in side reactions can beregenerated upon execution of a mild hydrolysis.

The C1,2 and/ or C6,7 fused methylene group is introduced by reaction ofthe conjugated unsaturated steroid with dimethylsulfoxonium methylidebase in dimethylsulfoxide. Alternatively, this group can be providedupon reductive dehalogenation, such as with lithium aluminum hydride, ofa halomethylene group, inserted as described above.

These groups can be inserted in a 3-keto-A -diene to give the C1,2adduct and a 3-keto-A -diene to give the C6,7 adduct. The bissubstituted derivatives are ideally prepared by first introducing thedesired group at C-1,2 and thereafter generating the A system andintroducing the desired group at C6,7.

The halomethylene and methylene groups so inserted are accomplished withthe orientation of the resultant fused grouping including both isomericalpha and beta configurations in variable ratios. Each isomer can beseparated and removed via conventional techniques, such aschromatography, fractional recrystallization, and the like, by virtue oftheir different physical properties. Although, in some instances, oneparticular configurational isomer may predominate in the reactionmixture; it will be understood that each, whether specifically mentionedor not, is included within the scope of the present invention.

The C3 elaboration follows after esterification at C17 has taken placeand the 3-keto function has been selectively reduced. This elaborationis performed by either conventional esterification procedures to givethe corresponding conventional hydrocarbon carboxylic acid esters or bytreatment of the 3B-hydroxyl group with dihydropyran or dihydrofuran togive the corresponding tet rahydropyran-2-y1 and tetrahydrofuran-Z-ylethers thereof, respectively. Treatment of the free hydroxyl group withsodium hydride and cyclopentyl bromide affords the 3/3-cyclopentylether.

Similarly, these ether groups can be introduced in the C17 position ifit is so desired.

The following examples illustrate the manner by which this invention canbe practiced and are not to be construed as limitations upon the overallscope hereof but rather as illustrations hereof.

EXAMPLE 1 To a solution of g. of pregn-4-en-17a-ol-3,20-dione in 100 ml.of anhydrous benzene are added 1 g. of ptoluene-sulfonic acid and ml. ofbicyclo[2.2.2]octanel-carboxylic acid chloride. The mixture is allowedto stand for 24 hours at room temperature and poured with stirring intoice and water. The organic phase is separated, washed with 10% sodiumcarbonate solution and with water, dried, and evaporated to yield17a-(bicyclo [2.2.2] octane-1 '-carbonyloxy) pregn-4-ene-3,20-dione andsome 318,170: bis(bicyclo[2.2.2]octane-1'-carbonyloxy) pregn-B-en-ZO-onewhich are separated by chromatography and further purified throughrecrystallization from etherzhexane.

A suspension of 1 g. of3B,17a-bis(bicyclo[2.2.2]octane-1'-carbonyloxy)pregn-3-en-20-one in 60ml. of methanol is treated with a solution of 1 g. of potassiumcarbonate in 6 ml. of water. The mixture is heated at reflux for onehour, cooled in ice and diluted with water. The solid which forms iscollected by filtration, washed with water and dried to yield170t-(blCyClO[2.2.2] octane-1-carbonyloxy)pregn-4-ene-3,20-dione whichis recrystallized from acetone:hexane.

By using 4-methylbicyclo[2.2.2]oct-ene-l-carboxylic acid chloride in theabove procedure, there is prepared the corresponding17a-(4'-methylbicyclo[2.2.2]oct-2-ene- 1'-carbonyloxy-pregn-4-ene-3,20-di0ne.

In a similar manner, the following compounds can be prepared from theappropriate starting compounds:

6-chloro-16-methyl-17a-(bicyclo [2.2.2]octane-1'-carbonyloxy)-19-norpregna-4,6-diene-3,20-dione, 6-chloro-16-methyl-17a- (4'-methylbicyclo [2.2.2] Oct-2-ene-1'-carbonyloxy-19-norpregna-4,6-diene-3,20-dione,6,16-dimethyl-17a-(bicyclo[2.2..2] octane-1'-carbonyloxy)-pregna-4,6-diene-3,20-dione, 6,16-dimethyl-l7a-(4'-methylbicyclo[2.2.2]oct-2'-ene- 1-carbonyloxy) -pregna-4,6-diene-3,20-dione,6,16-dimethyl-17-(bieyclo[2.2.2]octane-1-carbonyloxy)-19-norpregna-4,6-diene-3,20-dione,6,16-dimethyl-17a-(4'-methylbicyclo[2.2.2]oct-2-ene-1-carbonyloxy)-19-norpregna-4,6-diene-3,20-dione, 1700-(bicyclo[2.2.2]oetane-1-carbonyloxy) -19-norpregna-4,6-diene-20-dione,17w (4'-methylbicyclo [2.2.2]oct-2-ene-1'-carbonyloxy)19-norpregna-4,6-diene-3 ,20-dione, 6-chloro-17a-(bicyclo[2.2.2]octane-1'-carbonyloxy) 19-norpregna-4,6-diene-20-dione,-6-chloro-17a-(4-methylbicyclo[2.2.2] oct-2'-ene-1'-car bonyloxy)-19-norpregna-4,6-diene-20'dione, 6-ChlOIO-17a-(blCyClO [2.2.2]octane-1-carbonyloxy) pregn-4-ene-3,20-dione, 6-chloro17a-(4-methylbicyclo[2.2.2] oct-2'-ene-1'-carbonyloxy)-pregna-4-ene-3,20dione, 6-flUO1'O-17a-(biCyClO [2.2.2] octane-1'-carbonyloxy) pregna-4,6-diene-3,20-dione, 6-chloro-17a-(4'-methylbicyclo[2.2.2] oct-2'-ene-1'-carbonyloxy) -pregna-4,6-diene-3 ,20-dione,6-fluoro-17a-(bicyclo [2.2.2]octane-1-carbonyloxy)pregna-4,6-diene-3,20-dione, 6-fluoro-l7a- (4'-methylbicyclo[2.2.2]oct-2-ene-1'-carbonyloxy) -pre gn a-4,6-diene-3 ,20-dione, 6-methyl-l7a-(bicyclo [2.2.2] octane-1'-carbonyloxy) pregna-4,6-diene-3,20-dione,6-methyl-17u-(4-methylbicyclo [2.2.2] oct-2'-ene1- carbonyloxy-pregna-4,6-diene-3,20-dione, 6-methyl-17a-(bicyclo[2.2.2]octane-1'-carbonyloxy) pregna-4-ene-3,20-dione, 6-methyl- 17 a-4-methylbicyclo [2.2.2] oct-2'-ene-1-carbonyloxy) -pregna-4-ene-3,20-dione, 6-Ch010f-17a- (bicyclo [2.2.2]octane-1'-carbonyloxy) pregna-l ,4,6-triene-3,20-dione,

8 6-chloro-17u- (4'-methylbicyclo[2.2.2] oct-2-ene-lcarbonyloxy)-pregnal ,4,6-triene-3,20-dione, 16-methyl-l7a(bicyclo[2.2.2]octane-1'-carbonyloxy)- pregna-4,6-diene-3,ZO-dione, 16-methyl-17a-(4'-methylbicyclo [2.2.2] oct-2-ene-1'- car-bonyloxy)-pregna-4,6-diene-3 ,20-dione, 16-methyl-17a- (bicyclo[2.2.2]octane-l'-carbonyl0xy 19- nor-pregna-4,6-diene-3,20-dione,16-methyl-17a-(4'-methylbicyelo[2.2.2]oct-2'-ene-1'- carbonyloxy-l9-norpregna-4,6-diene-3,20-dione,6,7-difluoromethylene-17a-(4'methylbicyclo[2.2.2] oct-2'-ene-1'-carbonyloxy) -p1'egn-4-ene-3 ,ZO-dione,6,7-methylene-17a-(bicyclo[2.2.2] octane-1'-carbonyloxy)-pregn-4-ene-3,20-dione, 6,7-methylene-17a-(4'-methyl[2.2.2]octane-1'-carbonyioxy) -pregn-4-ene-3 ,20-dione,1,2-methylene-17a- (bicyclo[2.2.2] octane-1'-carbonyloxy -pregn-4-ene-3,ZO-dione, 1,2-methylene-l7a- (4'-methylbicyclo [2.2.2]octane-1'-carbonyloxy -pregn-4-ene-3,20-dione,1,Z-methylene-6,7-difluorornethylene-17a=(bicyclo[2.2.2]

octane-1'-carbonyloxy) -pregn-4ene-3,20-dione,1,2-methylene-'6,7-difluorornethylene- 17 u- (4-methylbicyclo [2.2.2]0ctane-1'-carbonyloxy)-pregn-4-ene- 3 ,ZO-dione, 6,7-dichloromethylene-17 0c- (bicyclo [2.2.2] octa ne- 1 carbonyloxy -pregn-4-ene-3,20-dione,6,7-dichloromethylene- 17 04- (4-methylbicyclo [2.2.2] octane-1'-ca1bonyloxy)-pregn-4-ene-3,20-dione,6,7-chloromethylene-17a-bicyclo[2.2.2]octane-1'-carbonyloxy-pregn-4-ene-3,20-di0zue, 6,7-chloromethylene-17a-(4-methylbicyclo[2.2.2] octane- 1'-carbonyloxy) pregn-4-ene-3,20-dione,6,7-fluoromethylene-17a-(bicyclo [2.2.2] 0ctane-1-car bonyloxy)-pregn-4-ene-3,20-dione, 6,7-fiuoromethylene- 1741- (4'-methylbicyclo[2.2.2] octane- 1'-carbonyloxy -pregn-4-ene-3 ,20-dione,6,7-chlorofluoromethylene-17a-(bicycl0 [2.2.2 octane- 1-carbonyloxy-pregn-4-ene-3,20-dione,6,7-chlorofiuoromethylene-17a-(4'-methylbicyclo[2.2.21

octanel-carbonyloxy -pregn-4ene-3 ,20'-dio.ne, and 6,7-difluoromethylene- 17oc- (bicyclo [2.2.2] octane- 1 carbonyloxy)-pregn-4-ene-3,20-dione,

as well as other corresponding 17a-mono ester derivatives containing thevarious possible substituents indicated in the above formulas.

Upon substitution of the appropriate substituted acid chloride (as setforth in the third paragraph of Example 5 infra.) in lieu of the otherbicyclo carboxylic acid chloride employed herein, the corresponding C-17mono ester of the corresponding starting steroid hydroxy compoundshereof are prepared.

EXAMPLE 2 A solution of 200 mg. of pregn-4-en-17rx-ol-3,20-dione in 32ml. of anhydrous isopropanol and 25 mg. of sodium borohydride is stirredat room temperature for 15 hours. One-hundred milliliters of water isadded and the resulting suspension is extracted several times withether. The ether phase is dried over sodium sulfate and evaporated todryness under reduced pressure to yield pregn-4-ene- 35,17wdi0l-20-onewhich may be further purified by recrystallization from ether.

A mixture of 2.5 g. of pregn-4-ene-3B,17u-diol-20-one in 15 ml. ofpyridine containing 4.0 g. of bicyclo[2.2.2] octane-l-carboxylic acidchloride is heated at steam bath temperature for about two hours. Themixture is then poured into ice water and the solid which formscollected by filtration, washed with water, and dried yielding 3 3-(bicyclo[2.2.2]octane-l-carbonyloxy) pregn-4-en-17aol-20-one.

A mixture of 2.5 g. of pregn-4-ene-3fi,17u-diol-20-one 10 ml. ofpyridine, 20 ml. of benzene, and 5.0 g. of 4-methylbicyclo[2.2.2]oct-2-ene-l-carboxylic acid chloride 9 is heated atreflux temperature for four hours. The mixture is then poured into iceWater, the solid which forms is collected by filtration, washed withWater, and dried to yield 35-(4methylbicyclo[2.2.2]oct-2'-ene-1'-carbonyloxy)-pregn-4-ene-l7a-ol-20-one.

In like manner, the corresponding 3B-mono esters of the othercorresponding steroid hydroxy compounds set forth in the fourthparagraph of Example 1 above are prepared, such as:

Upon substitution of the appropriate substituted acid chloride (as setforth in the third paragraph of Example in lieu of eitherbicyclo[2.2.2]octane-l-carboxylic acid chloride or4-methylbieyclo[2.2.2]oct-2-ene-l-carboxylic acid chloride in each ofthe procedures set forth above in the instant example, the correspondingC-3 mono esters of the corresponding starting steroid bishydroxycompounds hereof are prepared.

EXAMPLE 3 By following the procedure set forth in Example 2 above,utilizing bicyclo[2.2.2]octane-l-methylenechlorocarbonate in lieu ofbicyclo[2.2.2]octane-l-carboxylic acid chloride, there is prepared3/3-(bicyclo[2.2.2]octane-1'-methylenecarbonyldioxy)-pregn4-en-17a-ol-20-one.

Similarly, the corresponding3B-(bicyclo[2.2.2]octanel-methylenecarbonyldioxy) esters otherwisecorresponding to the other steroid compounds set forth in paragraph 4 ofExample 1 and the penultimate paragraph of Example 2 above, areprepared.

In like manner, upon substituting the otherbicyclomethylenechlorocarbonates prepared as set forth in Example 6,infra., the corresponding 3p-monobicyclochlorocarbonate derivatives ofthe above compound and those compounds set forth in Example 1 above, areprepared.

EXAMPLE 4 By utilizing the procedure outlined in Example 3 using,instead, tricyclo[3.3.l.1 ]decane-1 methylenechlorocarbonate, there isprepared 3B-(tricyclo[3.3.1.1 ]decane-1 methylenecarbonyldioxy)-pregn-4-en-17a-0l-20-one.

Similarly, the corresponding 3B-(tricyclo[3.3.1.1decane-l-methylenecarbonyldioxy) esters, otherwise corresponding to theother steroid compounds set forth in the fourth paragraph of Example 1and the penultimate paragraph of Example 2 above, are prepared.

EXAMPLE 5 A mixture of g. of bicyclo[2.2.2]octane-l-carboxylic acid, ml.of thionyl chloride in two drops of dimethylformamide, and about 40 ml.of benzene is heated at reflux temperature for about 2.5 hours. Theresultant mixture is then fractionally distilled to give bicyclo[2.2.2]octane-l-carboxylic acid chloride.

A mixture of 15 g. of 4-methy1bicyclo[2.2.2]oct-2-enel-carboxylic acid,25 ml. of thionyl chloride, and a drop of dimethylformamide is heated atreflux temperature for about 1.5 hours. Fractional distillation of thereaction mixture gives 4-methylbicyclo[2.2.2]oct 2 ene-l-carboxylic acidchloride.

Similarly, upon the substitution of other bicyclo[2.2.2]octane-l-carboxylic acids and other bicyclo[2.2.2]oct-2-ene-l-carboxylic acids in the procedures set forth in the immediatelypreceding two paragraphs, there is obtained the following correspondingacid chlorides:

bicyclo [2.2.2]oct-2-ene-l-carboxylic acid chloride,

4-methylbicyclo[2.2.2]octane-l-carboxylic acid chloride,

4-phenylbicyclo [2.2.2] oct-2-ene-1-carboxylic acid chloride,

4-phenylbieyclo[2.2.2]octane-l-carboxylic acid chloride,

4-n-propylbicyclo[2.2.2]octane-l-carboxylic acid chloride,

4-n-propylbicyclo [2.2.2] oct-Z-ene-l-carboxylic acid chloride,

4-ethylbicyclo [2.2.2] octane-l-carboxylic acid chloride,

4-ethylbicyclo [2.2.2] oct-2-ene-1-carboxylic acid chloride,

4-benzylbicyclo[2.2.2]octane-l-carboxylic acid chloride,

4-chlorophenylbicyclo[2.2.2]octane-l-carboxylic acid chloride,

4-chlorobicyclo[2.2.2]octane-l-carboxylic acid chloride,

4-chlorobicyclo [2.2.2] oct-2-ene-1-carboxylic acid chloride,

4-fluorobicyclo[2.2.2]octane-l-carboxylic acid chloride,

4-fluorobicyclo [2.2.2] oct-Z-ene-l-carboxylic acid chloride,

4-trifluoromethylbicyclo [2.2.2] octane-l-carboxylic acid chloride,

4-trifluoromethylbicyclo [2.2.2] oct-2-ene-1-carboxylic acid chloride,

4-cyanobicyclo[2.2.2]oetane-l-carboxylic acid chloride,

4-cyanobicyclo[2.2.2] oct-2-ene-1-carboxylic acid chloride,

4-acetoxybicyclo[2.2.2]octane-l-carboxylic acid chloride,

4-acetoxybicyclo [2.2.2] oct-2-ene-l-carboxylic acid chloride,

4-methoxybicyclo[2.2.2] octane-l-carboxylic acid chloride,

4-methoxybicyclo[2.2.2]oct-Z-ene-l-carboxylic acid chloride,

4-methoxymethylbicyclo[2.2.2]octane-l-carboxylic acid chloride,

4-methoxymethylbicyclo [2.2.2] oct-2-ene-1-carboxylic acid chloride,

4-acetoxymethylbicyclo [2.2.2] octane-l-carboxylic acid chloride, and

4-acetoxymethylbicyclo [2.2.2] oct-2-ene-1-carboxylic acid chlorideEXAMPLE 6 A solution of 1 g. sodium borohydride in 3 ml. of water isadded to an ice cooled solution of 1 g. of bicyclo[2.2.2]octane-l-carboxylic acid in ml. of methanol and the mixturethen allowed to stand for 16 hours at room temperature. The excessreagent is decomposed by addition of acetic acid and the solution isthen concentrated to small volume in vacuo and diluted with water. Theproduct is extracted with ethyl acetate and these ex tracts are washedwith water, dried, and evaporated to yieldbicyclo[2.2.2]octane-l-methylol which may be further purified byrecrystallization from acetonezhexane.

Bicyclo[2.2.2]octane-l-methylol (15.5 g.) is slowly added with stirringto 15 g. of liquid carbonyl chloride (phosgene) contained in a reactionvessel immersed in a Dry Ice-trichloroethylene bath. During theaddition, the temperature of the carbonyl chloride solution is kept ator below 0 C. After the addition is complete, the temperature of thesolution is allowed to slowly rise to room temperature. The mixture ismaintained at room temperature with stirring for from 10 to 15 hours,steps being taken to remove expelled carbonyl chloride. Thereafter, thereaction mixture is distilled under reduced pressure to givebicyclo[2.2.2]octane-1-methylenechlorocarbonate.

Similarly, the above procedures can be used to prepare the other C-2unsaturated and/ or C-4 substituted analogs thereof otherwisecorresponding to the derivatives set forth in the third paragraph ofExample 5 above, with the exception of the 4-cyano, 4-acyloxy, and4-acyloxymethyl derivatives.

EXAMPLE 7 The procedure set forth in Example 6 is repeated substitutingtricyclo[3.3.1.1 ]decane-l-carboxylic acid (adamantane-l-carboxylicacid) for bicyclo 2.2.2 octane-1- carboxylic acid thus givingtricyclo[3.3.1.1 ]decane-1- methylol initially and tricyclo[3.3.1.1]decane-1-methylenechlorocarbonate as a final product.

EXAMPLE 8 To a mixture of 10 g. of bicyclo[2.2.2]octane-l-carboxylicacid in a solution consisting of 25 ml. of ether and 10 ml. of pyridineis added a cold ether solution containing the chemical equivalent ofacetyl chloride. The reaction mixture is allowed to stand at 0 C. forfour hours and the resultant precipitate removed by filtration. Thesolution is washed with 25 ml. of concentrated hydrochloric acid, icewater, a 7% sodium hydroxide solution and again ice water. The washedsolution is dried at 0 C. over sodium sulfate, filtered, the etherevaporated to give bicyclo[2.2.2]octane-l-carboxylic acetyl anhydridewhich can be recrystallized from methanol.

Similarly, the other corresponding mixed anhydride starting compoundsare analogously prepared.

These derivatives can be substituted for the correspondind acidchlorides employed in Example 1 with similar results.

EXAMPLE 9 To a suspension of 1 g. dione in 7.5 ml. of anhydrous,peroxide-free dioxane are added 1.2 ml. of freshly distilled ethylorthoformate and 0.8 g. of p-toluenesulfonic acid. The mixture isstirred at room temperature for minutes and allowed to stand at roomtemperature for 30 minutes. There is then added 0.8 ml. of pyridine,followed by water until solidification occurs. This solid is collectedby filtration, washed with water, and air dried to yield 3,8ethoxypregna- 3,5(6)-dien-17a-ol-3,20-dione which is recrystallized fromacetone hexane.

A mixture of 5 g. of 3fi-ethoxypregna-3,5(6)-dien 17a-ol-3,20-di0ne, 2g. of anhydrous sodium acetate, and 100 ml. of acetone is treated with32 ml. of water. The solution is cooled to 5 C. and 1.1 molarequivalents of N-chlorosuccinimide and 2 ml. of glacial acetic acid areadded. The mixture is stirred for 30 minutes at the same temperature andthen diluted with water. After being allowed to stand at 0 C. for 15hours, the solid is. collected by filtration, washed with water, anddried under vacuum to yield 6B-chloropregn-4-en-17a-ol-3,20-dione whichis recrystallized from acetone. The corresponding 6a-chloro compound isobtained by dissolving this compound in glacial acetic acid andintroducing a slow stream of anhydrous hydrogen chloride over a periodof four hours and a temperature of 15 C. The solid which forms uponpouring this mixture into water is collected by filtration, washed withwater, and dried to yield 60cchloropregn-4-en-17a-ol-3,20-dione which isrecrystallized from acetone2hexane.

A stream of perchloryl fluoride is passed through a solution of 1 g. of3fi-ethoxypregna-3,5(6)-dien-17a-ol- 3,20-dione in 25 ml. ofdimethylformamide, cooled to 0 C. for five minutes. After being allowedto slowly attain a temperature of 20 C., the solution is poured intowater and extracted with ethyl acetate. These extracts are washed withsaturated aqueous sodium bicarbonate solution and With water toneutrality, dried over sodium sul fate and evaporated to dryness. Theresidue is then chromatographed on alumina to separate the 6oc-fil101Oand 6fl-fluoro isomers. The latter, which predominates,

is dissolved in 50 ml. of glacial acetic acid and through this solutionis passed a stream of dry hydrogen chloride for a period of 24 hours andat a temperature of 15 C. The mixture is poured into cold water and thesolid which forms is collected by filtration, washed with water, anddried to yiedd 6a-fluoropregn-4-en-17a-oi- 3,20-dione which isrecrystallized from acetonezhexane. In a similar manner, the other6-chloro and 6-fiuoro derivatives of the instant compounds are prepared.

EXAMPLE 10 To 120 ml. of acetone containing 1 g. of pregn-4-ene-16a,17a-diol-3-,20-dione are added 30 drops of 70% perchloric acid. Themixture is allowed to stand One hour at room temperature, 30 drops ofpyridine are added and the solution is evaporated to dryness underreduced pressure. Thirty milliliters of water are added to the residueand this mixture is extracted several times with ethyl acetate. Thecombined extracts are washed to neutrality with water, dried over sodiumsulfate and evaporated to dryness. The residue upon trituration withmethanol yields 16,17-isopropylidenedioxypregn-4-ene-3,20-dione which isrecrystallized from methanol.

Similarly, upon substitution of an alternate ketone or aldehyde in lieuof acetone in the preceding paragraph. there are obtained the otheralkylidenedioxy substituted compounds hereof. The other appropriatestarting steroids can be so elaborated.

A mixture of 1 g. of pregn-4-en-l7a-ol-3,20-dione, 1 g. ofp-toluenesulfonic acid monohydrate, 50 ml. of acetic acid, and 25 ml. ofacetic anhydride is allowed to stand at room temperature for 24 hoursand then is poured into water and stirred. This mixture is thenextracted with methylene chloride and these extracts are dried andevaporated. The residue is then dissolved in 250 ml. of methanolcontaining 5 ml. of concentrated hydrochloric acid. After refluxing forone hour, the mixture is neutralized with an aqueous 10% solution ofpotassium bicarbonate and evaporated. The residue is extracted withmethylene chloride, and the methylene chloride extract is washed withwater to neutrality, dried, and evaporated to yield17a-acetoxypregn-4-ene-3,20aiione which is recrystallized fromacetonezether.

To a solution of 5 g. of a pregn-4-en-17ot-ol-3,20-dione in ml. ofanhydrous benzene are added 1 g. of ptoluenesulfonic acid and 10 ml. ofpropionaldehyde. The mixture is allowed to stand for 24 hours at roomtemperature and poured with stirring into ice and water. The organicphase is separated, washed with 10% sodium carbonate solution and withwater, dried and evaporated to yield17a-propionyloxypregn-4-cue-3,20-dione which is further purified throughrecrystallization from etherzhexane.

A mixture of 2 g. of pregn-4-en-l7a-0l-3,20-dione in 8 ml. of pyridineand an equimolar amount of benzoyl chloride is heated at steam bathtemperatures for thirty minutes. The mixture is then poured into iceWater and the solid which forms is collected by filtration, washed withwater, and dried to yield 17a-benzoyloxypregn-4-enc- 3,20-dione which isfurther purified through recrystallization from methylenechloridezhexanc.

In like manner, the corresponding conventional hydrolyzable esters ofthe other compounds hereof, including those already containing a novelester hereof (and a free hydroxy group) are prepared by following theforegoing procedures. Others can be similarly prepared upon substitutingthe appropriate acid chloride, such as, for example, the adamantoyloxyester using adamantoyl chloride.

EXAMPLE 11 A mixture of 0.5 g. of pregn-4-en-l7a-ol-3,20-dione, 10 ml.of dioxane, and 0.135 g. of 2,3-dichloro-5,6-dicyano-l,4-benzoquinone isrefluxed for ten hours. The mixture is then cooled, filtered, andevaporated to dryness. The residue is dissolved in acetone and thissolution is then filtered through g. of alumina and concentrated toyield pregna-l,4-dien-17a-ol-3,20-dione which is further purified byrecrystallization from acetonezhexane.

A mixture of 1 g. of pregn-4-en-l7ot-ol-3,20-dione, 2 g. of chloranil,ml. of ethyl acetate and 5 ml. of acetic acid is refluxed under nitrogenfor 96 hours. The mixture is then cooled and washed with cold 10%aqueous sodium hydroxide until the washings are colorless. The organicsolution is dried over sodium sulfate and the ethyl acetate removed byevaporation. Upon chromatography of the residue on neutral alumina thereis obtained pregna- 4, 6 dien-17u-ol-3,20-dione which can be furtherpurified by recrystallization from acetone: hexane.

EXAMPLE 12 To a gently refluxing and stirred solution of 1 g. ofpregna-4,6-dien-17a-ol-3,20-dione in 8 ml. of dimethyl diethyleneglycolether is added in a dropwise fashion over a two-hour period, a solutionof equivalents of sodium chlorodifluoroacetate in 30 m1. of dimethyldiethyleneglycol ether. At the end of the reaction period, which may befollowed by the U.V. spectra, the mixture is filtered and evaporated invacuo to dryness. The solid which forms is collected, washed with water,dried, and chromatographed on alumina, eluting with methylene chlorideto yield 60:, 7a-difluoromethylenepregn-4-en-17u-ol-3,20-dione and6,8,75-difluoromethylenepregn-4-en-l7a-ol-3,20-dione.

By utilizing the other A compounds hereof, the 6,7- difiuorornethylenederivatives corresponding thereto are prepared.

Upon substituting the sodium trichloroacetate for sodiumchlorodifiuoroacetate in the above procedure, the corresponding6,7-dichloromethylene derivatives are prepared. Similarly, uponsubstitution of sodium dichlorofluoroacetate, sodium dichloroacetate,and sodium chlorofiuoroacetate of the above procedure, there arerespectively obtained the corresponding 6,7-chlorofiuoromethylene,6,7-chloromethylene, and 6,7-fluoromethylene derivatives.

EXAMPLE 13 A mixture of 7 g. of pregna-l,4-dien-17a-ol-3,20-dione, 25ml. of dry benzene, 5 ml. of ethylene glycol, and mg. ofp-toluenesulfonic acid monohydrate is refluxed for 16 hours using awater separator. The reaction mixture is then washed with aqueous sodiumbicarbonate solution and water, dried, and evaporated to dryness toyield 20,20 ethylenedioxy pregna-l,4-dien-l7a-ol-3-one which isrecrystallized from acetonezhexane.

A solution of 0.5 g. of 20,ZO-ethylenedioxypregna-1,4- dien-17a-ol-3-onein 5 ml. of dimethylsulfoxide is added to a solution of one equivalentof dimethylsulfoxonium methylide in dimethylsulfoxide, prepared in themanner of Corey et al., J. Am. Chem. Soc., 87, 1353 (1965). The mixtureis stirred under nitrogen and at room temperature for 20 hours and thenat 50 C. for seven hours. Fifty milliliters of water are then added andthe resulting mixture extracted four times with 50 ml. of ethyl acetate.The combined extracts are washed with water and saturated aqueous sodiumchloride solution, dried over sodium sulfate, and evaporated to dryness.This residue is then chromatographed on silica, eluting with ether:methylene chloride to yield 1a,2a-methy1ene-20,20-ethylenedioxypregn-4-en-17a-ol-3-one and its corresponding1,8,25-methylene isomer.

A mixture of 0.5 g. of1,2-methylene-20,20-ethylenedioxypregna-4-en-17a-ol-3-one in 30 ml. ofacetone and 50 mg. of p-toluenesulfonic acid is allowed to stand at roomtemperature for 15 hours. It is then poured into ice water and extractedwith ethyl acetate. These extracts are washed with water to neutrality,dried over sodium sulfate, and evaporated to dryness. The residue istriturated with ether to yield 1,2-methylenepregn-4-en-17aol-3,20-dionewhich is recrystallized from acetonezhexane.

Similarly, the 1,2-methylene derivatives of the other correspondingstarting compounds hereof are prepared.

The isomeric 6,7-methylene derivatives are analogously prepared from thecorresponding A starting compounds.

Upon introduction of the N system into the so produced 1,2-methylenecompounds and treating them according to the procedure set forth inExample 12 above, the corresponding 1,2 methylene-6,7-difluoromethylenecompounds are prepared.

EXAMPLE 14 To a solution of 1 g. of 17a-(bicycl0[2.2.2]octane-1'-carbonyloxy)-pregn-4-en-3fi-ol-20-one in 20 ml. of henzene, 20 ml. ofdihydrofuran is added. Five milliliters is distilled ofi? to removemoisture and the mixture is allowed to cool to room temperature. To thecooled mixture, 0.2 g. of freshly purified p-toluenesulfonyl chloride isadded. The mixture is stirred at room temperature for 24 hours and thenpoured into an excess of 5% aqueous sodium bicarbonate solution. Theproduct is extracted with ethyl acetate, the organic solution is washedwith water to neutrality, dried over anhydrous magnesium sulfate, andevaporated to dryness under reduced pressure. The oily residuecrystallizes on the addition of ether to yield3B-tetrahydrofuran-Z-yloxy- 17oz (bicyclo[2.2.2]octane-1carbonyloxy)-pregn-4-en- 20-one.

Two milliliters of dihydropyran are added to a solution of 1 g. of17m-(bicyclo[2.2.2]octane-1-carbonyloxy)- pregn-4-en-3fi-ol-20-one in 15ml. of benzene. About 1 ml. is removed by distillation to removemoisture and 0.4 g. of p-toluenesulfonyl chloride is added to the cooledsolution. This mixture is allowed to stand at room temperature for fourdays and is then washed with aqueous sodium carbonate solution andwater, dried, and evaporated. The residue is chromatographed on neutralalumina, eluting with hexane, to yield 3fi-tetrahydropyran- 2' yloxy 17a(bicyclo[2.2.2]octane-1-carbony1oxy)- pregn-4-en-20-one which isrecrystallized from pentane.

A solution of one chemical equivalent of 17a- (bicyclo [2.2.2]octane 1carbonyloxy)-pregn-4-en-3B-ol-20-one in 30 ml. of benzene is heated toreflux and about 2 ml. removed by distillation to eliminate moisture.The mixture is cooled to room temperature and two chemical equivalentsof sodium hydride are added, followed by the dropwise addition of twochemical equivalents of cyclopentyl bromide in 10 ml. of benzene over aperiod of 20 minutes, the mixture is allowed to reflux for 20 hoursafter which time the precipitate of sodium bromide is removed byfiltration and the organic phase dried and evaporated to yield3,6-cyclopentyloxy-17a-(bicyclo- [2.2.2]octane1'-carbonyloxy)-pregn-4-en-3fi-ol-20-one which is further purified uponrecrystallization from pentane.

In like manner, the foregoing etherification procedures can be practicedon the other 3B-hydroxy derivatives already bearing the 1711 novel monoester.

What is claimed is:

1. Compounds of the formula:

M I WE. Z R5 /\l/ L/V wherein:

R is an oxygen atom or the group in which R is hydroxy and theconventional hydrolyzable esters thereof, tetrahydropyran-Z-yloxy,tetrahydrofuran-Z-yloxy, cyclopentyloxy, or a polycyclic grouprepresented by one of the formulas:

16 and R is acetoxy, R is hydrogen, R is chloro, R is methyl, Z is acarbon-carbon single bond; and Z is a carbon-carbon double bond.

in which R is hydrogen, chloro, fluoro, trifluoromethyl, cyano,(lower)alkyloxy, acyloxy, (lower) alkyloxymethyl, acyloxymethyl,(lower)alkyl, or aryl; R is identical in meaning to R, exclusive ofcyano, acyloxy and acyloxymethyl; and Z is a carbon-carbon single bondor a carbon-carbon double bond;

R is hydrogen, hydroxy and the conventional hydrolyzable esters thereofor a polycyclic group represented by the formula:

in which each of R and Z is as already defined;

R is hydrogen, hydroxy, methyl, or when taken together with Ralkylidenedioxy;

R is hydrogen, chloro, fluoro, or methyl;

R is hydrogen or methyl;

each of Z and Z is a carbon-carbon single bond, at carbon-carbon doublebond, or a methylene group of the formula in which R is one of saidpolycyclic groups.

4. A compound according to claim 3 wherein R is the group in which R ismethyl; Z is a carbon-carbon single bond;

5. A compound according to claim 3 wherein R is the group in which R ismethyl, Z is a carbon-carbon single bond; and R is acetoxy, R ishydrogen, R is methyl, R is methyl, Z is a carbon-carbon single bond;and Z is a carbon-carbon double bond.

6. A compound according to claim 3 wherein R is the group in which R ismethyl, Z is a carbon-carbon single bond; and R is acetoxy, R ishydrogen, R is hydrogen, R is methyl, Z is a carbon-carbon single bond;and Z is a carbon-carbon single bond.

7. A compound according to claim 3 wherein R is the group in which R ismethyl, Z is a carbon-carbon double bond; and R is acetoxy, R ishydrogen, R is chloro, R is methyl, Z is a carbon-carbon single bond;and Z is a carbon-carbon double bond.

8. A compound according to claim 3 wherein R is the group LLO- in whichIR is methyl; Z is a carbon-carbon double bond; and R is acetoxy, R ishydrogen, R is methyl, R is methyl, Z is a carbon-carbon single bond;and Z is a carbon-carbon double bond,

9. A compound according to claim 3 wherein R is the group agile in whichR is methyl, Z is a carbon-carbon double bond; and R is acetoxy, R ishydrogen, R is hydrogen, R is methyl, Z is a carbon-carbon single bond;and Z is a carbon-carbon single bond.

10. A compound according to claim 3 wherein R is the group in which R ismethyl, Z is a carbon-carbon single bond; and R is hydrogen, R isu-methyl, R is chloro, R is methyl, Z is a carbon-carbon single bond,and Z is a carbon-carbon single bond.

11. A compound according to claim 3 wherein R is the group R Q fio-- inwhich R is methyl, Z is a carbon-carbon single bond; and R is hydrogen,R is wmethyl, R is fi-methyl, R is methyl, Z is a carbon-carbon singlebond, and Z is a carbon-carbon single bond.

12. A compound according to claim 3 wherein R is the group in which R ismethyl, Z is a carbon-carbon double bond; and R is hydrogen, R iscit-methyl, R is chloro, R is methyl, Z is a carbon-carbon single bond,and Z is a carbon-carbon single bond.

13. A compound according to claim 3 wherein R is the group in which R ismethyl, Z is a carbon-carbon double bond; and R is hydrogen, R isa-methyl, R is fi-methyl, R is methyl, Z is a carbon-carbon single bond,and Z is a carbon-carbon single bond.

14. A compound according to claim 3 wherein R is the group in which R ismethyl, Z is a carbon-carbon single bond; and R is acetoxy, R ishydrogen, R is methyl, R is methyl, Z is a carbon-carbon single bond;and Z is a carbon-carbon double bond.

16. A compound according to claim 3 wherein R is the group in which R ismethyl, Z is a carbon-carbon single bond; and R is acetoxy, R ishydrogen, R is hydrogen, R is methyl, Z is a carbon-carbon single bond;and Z is a carbon-carbon single bond.

17. A compound according to claim 3 wherein R is the group in which R ismethyl, Z is a carbon-carbon double bond; and R is acetoxy, R ishydrogen, R is chloro, R is methyl, Z is a carbon-carbon single bond;and Z is a carbon-carbon double bond.

18. A compound according to claim 3 wherein R is the group in which R'is methyl, Z is a carbon-carbon double bond, and R is acetoxy, R ishydrogen, R is methyl, R is methyl, Z is a carbon-carbon single bond;and Z is a carbon-carbon double bond.

19. A compound according to claim 3 wherein R is the group in which R ismethyl, Z is a carbon-carbon double bond, and R is acetoxy, R ishydrogen, R is hydrogen, R is methyl, Z is a carbon-carbon single bond;and Z is a carbon-carbon single bond.

20. A compound according to claim 3 wherein R is the group in which R ismethyl, Z is a carbon-carbon single bond; and R is hydrogen, R ism-methyl, R is chloro, R is methyl, Z is a carbon-carbon single bond,and Z is a carbon-carbon single bond.

21. A compound according to claim 3 wherein R is the group in which R ismethyl, Z is a carbon-carbon double bond; andiR is hydrogen, R isa-methyl, R is chloro, R is methyl, Z is a carbon-carbon single bond,and Z is a carbon-carbon single bond.

23. A compound according to claim 3 wherein R is the group in which R ismethyl, Z is a carbon-carbon double bond;

and R is hydrogen, R is u-methyl, R is 8-methyl, R is methyl, Z is acarbon-carbon single bond, and Z is a carbon-carbon single bond.

24. A compound according to claim 3 wherein R is the group and R isacetoxy, R is hydrogen, R is chloro, R is methyl, Z is a carbon-carbonsingle bond, and Z is 1 carbon-carbon double bond.

25. A compound according to claim 3 wherein R is the group and R isacetoxy, R is hydrogen, R is methyl, R [S methyl, Z is a carbon-carbonsingle bond, and Z is a carbon-carbon double bond.

26. A compound according to claim 3 wherein R is the group and R isacetoxy, R is hydrogen, R is hydrogen, R [S methyl, Z is a carbon-carbonsingle bond, and Z is a carbon-carbon single bond.

27. A compound according to claim 3 wherein R is the group and R ishydrogen, R is a-methyl, R is chloro, R is methyl, Z is a carbon-carbonsingle bond, and Z is carbon-carbon single bond.

28. A compound according to claim 3 wherein R is the group l CH2 0 coand R is hydrogen, R is a-methyl, R is B-methyl, R is methyl, Z is acarbon-carbon single bond, and Z is a carbon-carbon single bond.

No references cited.

ELBERT L. ROBERTS, Primary Examiner U.S. Cl. X.R.

